Cancer is a major cause of death and severe trauma in modern society. Cancer afflicts the young, old, males, females and peoples of all races may contract cancer, although cancer in children is relatively rare, perhaps with the exception of childhood leukemia. In western society, cancer of the colon and lung cancer are major diseases. In women, breast cancer is the most common form of cancer.
Many cancers are accompanied by overproduction of human mucin. Mucins are heavily glycosylated proteins (greater than about 100 kilodalton (kD) which are produced by many epithelial cells and tumors (Gendler et al., J. Biol. Chem, 263:12820-12823, 1988). Mucins found on cancer cells are different in some respects to those on normal epithelial cells, in that some mucins have a deficiency in their carbohydrate coat which leaves the protein core exposed (Harisch et al., J. Biol. Chem., 264:872-883, 1989). There are seven forms of known human mucin designated MUC1, MUC2, MUC3, MUC4, MUC5, MUC6 and MUC7 (Marjolijn et al., J. Biol. Chem., 265:5573-5578, 1990; Crocker et al., Br. J. Cancer, 55:651-652, 1987; Apostolopoulos et al., Crit. Rev. Immunol., 14:293-309, 1994; and Bobek et al., J. Biol. Chem., 268:20563-20569, 1993). MUC1 is the most ubiquitous. The various mucins all have very similar properties, that is, they are transmembrane glycoproteins, all having a variable number of repeated amino acid sequences, which have a high content of serine, threonine and proline. Overproduction of aberrantly glycosylated mucins (either non-glycosylated or a deficiency in glycosylation) is characteristic of tumors of the breast, ovary, pancreas, colon, lungs, prostate and other tumors of secretory tissue. The copy DNA (cDNA) sequences of the respective protein cores of the human mucins MUC1 to MUC7 have been cloned and characterized and have been found to contain highly repetitive central portions of varying numbers of repeats of particularly amino acid motifs (known as VNTR's). By way of example, MUC1 consists of unique amino and carboxyl terminal sequences separated by a highly repetitive central portion containing forty to eighty tandemly arranged copies or repeats of a twenty amino acid motif. The VNTR's of MUC1 through MUC7 are set forth below:
MUC1 VNTR- SAPDTRPAPGSTAPPAHGVT(SEQ ID NO: 1) MUC2 VNTR- PTTTPISTTTMVTPTPTGTQT(SEQ ID NO: 2) MUC3 VNTR- HSTPSFTSSITTTETTS(SEQ ID NO: 3) MUC4 VNTR- TSSASTGHATPLPVTD(SEQ ID NO: 4) MUC5 VNTR- PTTSTTSA(494 base pair insert - eight amino acid tandemrepeat) MUC6 VNTR- 169 amino acid repeat unit(SEQ ID NO: 5) MUC7 VNTR- TTAAPPTPPATTPAPPSSSAPPE(SEQ ID NO: 6)
The repeated subunit of MUC6 comprises 169 amino acids, although at this time the amino acid sequence of this repeat unit has not been fully characterized. The MUC7 sequence has recently been published (Bobek et al., ibid.).
Finn and colleagues have demonstrated that in the lymph nodes of patients with breast cancer (Barnd et al., Proc. Natl. Acad. Sci USA, 86:7159-7163, 1989; and Jerome et al., in Cell. Immunity and Immunotherapy of Cancer, pp. 321-328, 1990), cancer of the pancreas, ovary and other tumors, cytotoxic lymphocytes are present which react with human mucin. Antibodies to the MUC1 peptide can block the activity of these cytotoxic T lymphocytes on MUC1 and target cells (Barnd et al., ibid.; and Jerome et al., ibid.). Recently, cytotoxic lymphocytes to a murine lung cancer have also been described (Mandelboimo et al., Nature, 369:67-71, 1994).
The surgery associated with tumor removal is traumatic to the patient, often disfiguring, and costly. Established chemotherapeutic and radiation procedures for tumor treatment which may be carried out in place of, or in conjunction with, surgical procedures are often debilitating and associated with severe side-effects. There is accordingly an urgent need for immunoregulatory compositions and methods for the prevention/treatment of tumors.
There is an urgent need for new compositions and methods for the treatment of cancer. Similarly, there is a pressing need for alternative compositions and methods for the treatment of other disease states such as type I allergies, malaria, HIV, dental caries, flu, cholera, foot and mouth disease, meningitis, Leishmania infection, whooping cough, rabies, Streptococcus infection, respiratory infection, measles, Lyme disease, tuberculosis, bacterial meningitis, shingles, rubella, hepatitis, herpes, hepatitis A, polio, venereal disease/trachoma, hepatitis B, common cold, cervical cancer, meningitis/pneumonitis, chicken pox, small pox and pneumonia/PUO.